Several controlled clinical studies have reported that multiple sclerosis (MS) patients develop major depressive episodes at a rate higher than other neurologic diseases of comparable severity. Preliminary clinical and epidemiologic data from this medical center confirm these reports. This project proposes a search of the underlying neurobiologic mechanisms associated with MS which might explain the depressive symptomatology. Sixty MS patients have already been tentatively identified as research subjects. Thirty of these have demonstrated vulnerability to major depressive symptomatology with onset after the diagnosis of MS. Thirty will be disability matched controls without mood disorders. A comparative investigation will be conducted of those parameters which are most likely to distinguish the MS-depression study group from the controls: HLA type, CSF immune complexes, CSF catecholamines, CSF monoamine metabolites, CT/NMR scanning for region-of-interest damage, and neuropsychologic testing. When depressive relapses occur, subjects will be reinvestigated for evidence of neuroanatomic or neurophysiologic alteration. A double blind, placebo controlled trial of nortriptyline will be conducted upon the relapse group, to determine pharmacologic response properties of these depressions. Emotional states are brain states. The underlying neurobiologic mechanisms of emotion may come to be understood through an investigation of neurologic models for behavioral disorders. Multiple sclerosis may represent a neurologic model of depression.